Although, the biological and medical value of identifying the genes and variants responsible for Mendelian disorders is extraordinarily high, the vast majority of these remain unexplained at the molecular level. To this end, we will create a partnership between two of the oldest and most accomplished human genetics programs in the country, those at Baylor College of Medicine (BCM) and Johns Hopkins University School of Medicine (JHUSOM), to form the Baylor-Hopkins Center for Mendelian Genomics (BHCMG). In doing so, we will take advantage of our complete access to OMIM and of the synergies afforded by combining our expertise in clinical genetics, genomic technologies, genetic analysis and understanding the biological basis of genetic disease. We will meet the challenge of finding and recruiting samples representing these rare disorders by creating and utilizing a worldwide network of colleagues and former trainees to identify and recruit thousands of patients and families with unexplained Mendelian phenotypes or with undiagnosed disease that segregates in their families as Mendelian traits. We already have >2,000 DNA samples in hand at our two institutions and have identified > 12,000 DNA samples in our network of 17 collaborators around the world. Moreover, we have developed strategies to utilize OMIM (>10, 000 unique hits/day) to flag unexplained phenotypes and recruit samples. We will further organize our efforts by building a sample and disease-tracking database that is integrated with and accessible through OMIM as well as through a BHCMG web site and have assembled a committee of experts to assist with the inevitable ELSI issues. We will build on our existing high throughput genotyping and sequencing pipelines to develop an integrated laboratory effort and we will use a committee of experts from both institutions plus outside experts to analyze the data and develop new software tools to advance the field. Finally, to disseminate the phenotypic and molecular information we will follow an aggressive plan of data dissemination using OMIM and other web-based resources as well as organizing an annual Mendelian genetics meeting open to all.